The development of new collateral blood vessels to provide blood flow to ischemic tissue is an extremely complex process that occurs as a result of several distinct processes including sprouting of new blood vessels from existing vascular structures, migration of bone marrow-derived endothelial precursor cells to sites of ischemia, recruitment of inflammatory cells, and arterialization of endothelial channels (both existing and newly formed) with vascular smooth muscle cells. While much has been learned about the involvement of growth factors such as VEGF and bFGF the precise molecular mechanisms underlying adaptive vascular growth are extremely complex and remain incompletely understood. The secreted phosphoprotein osteopontin, well known as a modulator of bone remodeling, is being considered in the present study for its potential role in reparative angiogenesis. Circumstantial evidence supporting a possible role for osteopontin in vascular growth comes from several sources including the observations that osteopontin supports cell migration, prevents apoptosis of endothelial cells and is growth promoting for smooth muscle cells. In addition, osteopontin is a ligand for 1v21-3 integrins which are known to be important in cell survival and neovascularization. These data are supported by the observations that wound healing (a process that may involve angiogenesis) is impaired in osteopontin deficient (OPN-/-) mice. Furthermore, recent studies employing transfected murine neuroblastoma cells secreting high levels of osteopontin show that osteopontin enhances local angiogenesis and promotes tumor growth. It has also been shown that expression of osteopontin correlates with progression of gastric, breast and lung cancers. Conversely, osteopontin deficiency has been shown to reduce experimental tumor cell metastasis to bone and soft tissues and to reduce resorption of implanted ectopic bone secondary to reduced vascularization. We have recently shown that osteopontin positively modulates vascular inflammatory processes which suggest an additional important mechanism through which osteopontin can enhance neovascularization in the adult. Based on these circumstantial data, we hypothesize that osteopontin plays a pivotal role in postnatal vascular growth. We propose to make use of osteopontin deficient mice to define the functional role of osteopontin in new vessel formation and to further define the contributions of inflammatory responses to this process. PUBLIC HEALTH RELEVANCE: The development of new blood vessels in the adult is an important mechanism through which the adult can compensate for blockages in blood vessels that are caused by atherosclerosis. This work will study osteopontin, an important protein that is thought to be very important in regulating this process. The ultimate goal is to develop better therapeutic approaches to treating patients with atherosclerosis.